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CRel Expression Regulates Distinct Transcriptional and Functional Profiles Driving Fibroblast Matrix Production in Systemic Sclerosis

ABSTRACT: cRel Expression Regulates Distinct Transcriptional and Functional Profiles Driving Fibroblast Matrix Production in Systemic Sclerosis

PROVIDER: PRJNA635919 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11878436_1.fastq.gz	Fastqsanger.gz
	SRR11878436_2.fastq.gz	Fastqsanger.gz
	SRR11878437_1.fastq.gz	Fastqsanger.gz
	SRR11878437_2.fastq.gz	Fastqsanger.gz
	SRR11878438_1.fastq.gz	Fastqsanger.gz

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Single-cell analysis reveals fibroblast heterogeneity and myofibroblasts in systemic sclerosis-associated interstitial lung disease

Project description:Myofibroblasts are key effector cells in the extracellular matrix remodeling of systemic sclerosis-associated interstitial lung disease (SSc-ILD), however the diversity of fibroblast populations present in the healthy and SSc-ILD lung is unknown, and has prevented the specific study of the myofibroblast transcriptome. We sought to identify and define the transcriptomes of myofibroblasts and other mesenchymal cell populations in human healthy and SSc-ILD lungs to understand how alterations in fibroblast phenotypes lead to SSc-ILD fibrosis.

2019-08-14 | GSE128169 | GEO

Myofibroblast transcriptome indicates SFRP2+ fibroblast progenitors in systemic sclerosis skin

Project description:Skin and lung fibrosis in systemic sclerosis (SSc) is driven by myofibroblasts, alpha-smooth muscle actin (SMA) expressing cells that produce matrix as well as increase tension on surrounding tissues. Myofibroblast progenitors have been described to arise from a variety of cell types in murine fibrosis models, but relatively modest insight is available as to their source and differentiation in fibrotic human diseases. We utilize single cell RNA-sequencing to examine the transcriptome changes that occur in fibroblasts in SSc skin and during myofibroblast differentiation. We show that dermal myofibroblasts arise from an SFRP2/DPP4-expressing progenitor fibroblast population. In SSc skin, fibroblasts undergo global changes in gene expression, including SFRP2-expressing fibroblasts, which globally upregulate expression of markers, such as PRSS23 and THBS1. However, only a fraction of SSc fibroblasts differentiate into myofibroblasts, as shown by expression of additional markers, such as SFRP4 and FNDC1. These results indicate that myofibroblasts derive from a specific fibroblast subpopulation in SSc skin, that their differentiation proceeds in two stages and that other fibroblast populations also shift transcriptomes in SSc skin, suggesting a cytokine driven process. The myofibroblast transcriptome implicates upstream transcription factors that should help further unravel the drivers of myofibroblast differentiation.

2021-05-20 | GSE138669 | GEO

Myofibroblast transcriptome indicates SFRP2+ fibroblast progenitors in systemic sclerosis skin

Project description:Myofibroblast transcriptome indicates SFRP2+ fibroblast progenitors in systemic sclerosis skin

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cRel Expression Regulates Distinct Transcriptional and Functional Profiles Driving Fibroblast Matrix Production in Systemic Sclerosis

Project description:The scope of this project is to investigate transcriptional differences bewteen wild type and Rel-/- fibroblasts under basal conditions. Mouse fibroblasts were isolated via explant culture from skin and lungs of un-challenged mice.

2020-05-30 | GSE151469 | GEO

IgG from systemic sclerosis patients induce a profibrosing and serotype-dependent phenotype in normal dermal fibroblast: a multi-omics study

Project description:Autoantibodies (Aab) are frequent in systemic sclerosis (SSc). While recognized as potent biomarkers, their pathogenic role is much debated. This study explored the effect of purified IgG from SSc patients on the phenotype and function of healthy dermal fibroblast (FB) using an innovative multi-omics approach.

2022-06-29 | PXD025885 | Pride

Attenuation of Fibroblast Activation and Fibrosis by Adropin in Systemic Sclerosis (SSc)

Project description:Attenuation of Fibroblast Activation and Fibrosis by Adropin in Systemic Sclerosis (SSc)

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Attenuation of Fibroblast Activation and Fibrosis by Adropin in Systemic Sclerosis (SSc)

Project description:Attenuation of Fibroblast Activation and Fibrosis by Adropin in Systemic Sclerosis (SSc)

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Impaired TFAM expression promotes mitochondrial damage to drive fibroblast activation and fibrosis in systemic sclerosis

Project description:Objectives: The transcription factor TFAM is controlling the transcription of core proteins required for mitochondrial homeostasis. The aim of the current study was to investigate changes in TFAM expression in systemic sclerosis (SSc), to analyze mitochondrial function and to evaluate the consequences for fibroblast activation. Methods: The expression of TFAM was analyzed by immunofluorescence and Western blot. The effects of TFAM knockout were investigated in cultured fibroblasts and in bleomycin-induced skin and lung fibrosis and in TβRIact-induced skin fibrosis. Results: The expression of TFAM was downregulated in fibroblasts in SSc skin and in cultured SSc fibroblasts. The downregulation of TFAM was associated with decreased mitochondrial number and accumulation of damaged mitochondria with release of mtDNA, accumulation of deletions in mtDNA, metabolic alterations with impaired OXPHOS and release of the mitokine GDF15. Chronic, but not acute exposure of normal fibroblasts to TGFβ mimicked the finding in SSc fibroblasts with downregulation of TFAM and accumulation of mitochondrial damage. Downregulation of TFAM promotes fibroblast activation with upregulation of fibrosis-relevant GO-terms in RNASeq. Mice with fibroblast-specific knockout of TFAM are prone to fibrotic tissue remodeling with fibrotic responses even to NaCl instillation and enhanced sensitivity to bleomycin injection and TβRIact-overexpression. TFAM knockout fosters SMAD3 signaling to promote fibroblast activation. Conclusions: Alterations in the key mitochondrial transcription factor TFAM in response to prolonged activation of TGFβ and associated mitochondrial damage induce transcriptional programs that promote fibroblast-to-myofibroblast transition and drive tissue fibrosis.

2021-12-21 | GSE184356 | GEO

Gene expression from human keratinocytes isolated from limited systemic sclerosis (lcSSc) and diffuse systemic sclerosis (dcSSc) skin biopsy

Project description:Systemic sclerosis (SSc) is a rare but devastating disease of fibrosis impacting the dermis and multiple organ systems. The prevalence ranges from 4 to 489 cases per million individuals with ten year mortality rates reported around 18 percent. Survival is related to the extent of skin involvement, yet the precise mechanisms driving skin fibrosis in SSc remain unknown. In this study, we analyzed the shared and unique transcriptomic profiles of SSc and normal keratinocytes.

2018-03-21 | GSE81072 | GEO

Attenuation of Fibroblast Activation and Fibrosis by Adropin in Systemic Sclerosis (SSc)

Project description:Fibrotic diseases impose a major socioeconomic challenge on modern societies with limited treatment options. Adropin, a peptide hormone encoded by the energy-homeostasis-associated (ENHO) gene, is implicated in metabolism and vascular homeostasis, but its role in the pathogenesis of fibrosis remains enigmatic. Here, we used machine learning approaches in combination with functional in vitro and in vivo experiments to characterize Adropin/ENHO as a potential regulator involved in fibroblast activation and tissue fibrosis in systemic sclerosis (SSc). We demonstrated consistent downregulation of Adropin/ENHO in SSc skin across different SSc cohorts. The prototypical profibrotic cytokine TGFβ reduced Adropin/ENHO expression in a JNK-dependent manner. Restoration of Adropin signaling by therapeutic application of bioactive Adropin34-76 peptides in turn inhibited TGFβ-induced fibroblast activation and fibrotic tissue remodeling in primary human dermal fibroblasts, three-dimensional full-thickness skin equivalents, the mouse models of bleomycin-induced pulmonary fibrosis and sclerodermatous chronic graft-versus-host-disease (sclGvHD), and precision-cut human skin slices (PCSS). Knockdown of GPR19, receptor of Adropin, abrogated the antifibrotic effects of Adropin in fibroblasts. RNA-seq demonstrated that the antifibrotic effects of Adropin34-76 were functionally linked to deactivation of GLI1 dependent profibrotic transcriptional networks, which was experimentally confirmed in vitro, in vivo and ex vivo. ChIP-seq confirmed Adropin34-76-induced changes in TGFβ/GLI1 signaling. Our study thus characterizes the TGFβ-induced downregulation of Adropin/ENHO expression as a potential pathomechanism of SSc as a prototypical systemic fibrotic disease that unleashes uncontrolled activation of profibrotic GLI1 signaling. We also provide evidence in multiple preclinical models that Adropin34-76 might offer potential for the treatment of fibrosis.

2024-04-29 | GSE252139 | GEO

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